Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination

Ved P. Sharma, Binwu Tang, Yarong Wang, Camille L. Duran, George S. Karagiannis, Emily A. Xue, David Entenberg, Lucia Borriello, Anouchka Coste, Robert J. Eddy, Gina Kim, Xianjun Ye, Joan G. Jones, Eli Grunblatt, Nathan Agi, Sweta Roy, Gargi Bandyopadhyaya, Esther Adler, Chinmay R. Surve, Dominic Esposito, Sumanta Goswami, Jeffrey E. Segall, Wenjun Guo, John S. Condeelis (), Lalage M. Wakefield () and Maja H. Oktay ()
Additional contact information
Ved P. Sharma: Albert Einstein College of Medicine
Binwu Tang: National Cancer Institute
Yarong Wang: Albert Einstein College of Medicine
Camille L. Duran: Albert Einstein College of Medicine
George S. Karagiannis: Albert Einstein College of Medicine
Emily A. Xue: Albert Einstein College of Medicine
David Entenberg: Albert Einstein College of Medicine
Lucia Borriello: Albert Einstein College of Medicine
Anouchka Coste: Albert Einstein College of Medicine
Robert J. Eddy: Albert Einstein College of Medicine
Gina Kim: Albert Einstein College of Medicine
Xianjun Ye: Albert Einstein College of Medicine
Joan G. Jones: Albert Einstein College of Medicine
Eli Grunblatt: Yeshiva University
Nathan Agi: Yeshiva University
Sweta Roy: Yeshiva University
Gargi Bandyopadhyaya: Yeshiva University
Esther Adler: NYU Langone Medical Center
Chinmay R. Surve: Albert Einstein College of Medicine
Dominic Esposito: Frederick National Laboratory for Cancer Research
Sumanta Goswami: Albert Einstein College of Medicine
Jeffrey E. Segall: Albert Einstein College of Medicine
Wenjun Guo: Albert Einstein College of Medicine
John S. Condeelis: Albert Einstein College of Medicine
Lalage M. Wakefield: National Cancer Institute
Maja H. Oktay: Albert Einstein College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-24

Abstract: Abstract Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.

Date: 2021
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DOI: 10.1038/s41467-021-27308-2

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